The Importance of Abnormal Inflammasome Activation as a Risk Factor between Traumatic Brain Injury and Alzheimer’s Disease

异常炎症体激活作为创伤性脑损伤和阿尔茨海默病之间危险因素的重要性

• 批准号: 10700483
• 负责人: JUAN Pablo DE RIVERO VACCARI
• 金额: $ 167.13万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700483
• 关键词: Importance; Abnormal; Inflammasome; Activation; Risk

Traumatic brain injury (TBI) is a risk factor for the development of Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (AD/ADRD). Although much work has been done in evaluating pathophysiological mechanisms of TBI and AD, the relationships between these two conditions is not completely understood. The role of inflammation in the pathophysiology of TBI and neurodegenerative diseases has been reported in the experimental and clinical literature. Accordingly, TBI and neurodegenerative diseases share many pathological and immunological hallmarks that indicate potential relationships that are critical as therapeutic strategies are developed. Recently, our laboratories, as well as others, have helped clarify the importance of abnormal inflammasome signaling in the pathogenesis of TBI and in the aging brain. These findings indicate that an innate inflammatory response plays a critical role in multiple pathophysiological events in neurodegenerative diseases such as AD. New evidence for the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-specks from microglial cells has provided further evidence for inflammasome activation in AD. Importantly, ASC- specks with prion-like properties contribute to the deleterious effects of the innate immune response mediated by the inflammasome. The overall goal of the proposed studies is to determine mechanisms underlying TBI-induced inflammasome activation as a risk factor for AD and to evaluate targeted therapeutic approaches to improve outcomes in this patient population. Our central hypothesis is that inflammasome activation in AD augments TBI-induced inflammation by a mechanism, mediated in part by extracellular vesicle (EV) containing inflammasome proteins and ASC-speck accumulation, that contributes to worsened AD pathology and memory impairments. To test this hypothesis the following aims will be pursued: Aim 1) To determine the temporal profile and the mechanisms underlying the detrimental effects of TBI on inflammasome activation in AD mice; Aim 2) To investigate the role of abnormal inflammasome activation and ASC-specks in microglia as an underlying mechanism for the deleterious effects of TBI in AD mice and Aim 3) To determine the therapeutic effects of inflammasome inhibition and ASC-speck formation on histopathological and behavioral outcomes after TBI in WT and AD-transgenic mice. The proposed studies will provide new information on how specific genetic risk factors for AD may heighten TBI- induced neurodegenerative processes and lead to AD-related pathological and progressive cognitive decline. Moreover, these studies will advance current inflammasome research into the AD/ADRD field to elucidate novel mechanisms underlying how TBI contributes to the onset of neurodegenerative disorders, and provide a new direction for evaluating therapeutic interventions targeting abnormal inflammasome activation after TBI in AD-transgenic mice for potential translation to the clinic.

创伤性脑损伤（TBI）是阿尔茨海默氏病（AD）和阿尔茨海默病发展的危险因素 尽管在评估疾病相关痴呆症（AD/ADRD）方面已经做了很多工作。 TBI 和 AD 的病理生理机制，这两种情况之间的关系并不 炎症在 TBI 和神经退行性病变的病理生理学中的作用已完全了解。 相应地，TBI 和 TBI 疾病已在实验和临床文献中得到报道。 神经退行性疾病有许多共同的病理和免疫学特征，表明它们具有潜在的潜力 最近，我们的实验室以及治疗策略的制定都至关重要。 其他人，有助于阐明异常炎性体信号传导在 TBI 发病机制中的重要性 这些发现表明，先天性炎症反应在衰老的大脑中发挥着关键作用。 AD 等神经退行性疾病中的多种病理生理事件。 释放含有半胱天冬酶募集结构域 (ASC) 的凋亡相关斑点样蛋白 - 斑点 来自小胶质细胞的 ASC- 为 AD 中炎症小体的激活提供了进一步的证据。 具有类似朊病毒特性的斑点会导致先天免疫反应的有害影响 所提出的研究的总体目标是确定机制。 潜在的 TBI 诱导的炎症小体激活作为 AD 的危险因素并评估目标 我们的中心假设是改善该患者群体的治疗方法。 AD 中炎症小体的激活通过某种机制增强 TBI 诱导的炎症，部分介导 含有炎性体蛋白和 ASC 斑点积累的细胞外囊泡 (EV)，有助于 为了验证这一假设，我们将实现以下目标： 追求：目标 1) 确定痛苦影响的时间概况和机制 TBI对AD小鼠炎症小体激活的影响；目的2)研究异常炎症小体的作用 小胶质细胞中的激活和 ASC 斑点作为 TBI 有害影响的潜在机制 AD 小鼠和目标 3) 确定炎性体抑制和 ASC-speck 的治疗效果 WT 和 AD 转基因小鼠 TBI 后组织病理学和行为结果的形成。 拟议的研究将提供有关 AD 的特定遗传风险因素如何加剧 TBI 的新信息 诱导神经退行性过程并导致 AD 相关的病理和进行性认知 此外，这些研究将推动当前炎症体研究进入 AD/ADRD 领域。 阐明 TBI 如何导致神经退行性疾病发生的新机制，以及 为评估针对异常炎症体激活的治疗干预措施提供新方向 AD 转基因小鼠 TBI 后可能转化为临床。